Jurnal Gagal Jantung Print

(Hellenic Journal of Cardiology) HJC • 227

Hellenic J Cardiol 2011; 52: 227-235

Manuscript received:August 19, 2010;Accepted:September 15, 2010.

Address:Emad F. Aziz

The ACAP Program St. Luke’s Roosevelt Hospital Center Columbia University College of Physicians & Surgeons, 1111 Amsterdam Ave, New York, NY 10025, USAe-mail: [email protected]

Key words: Critical pathway, acute decompensated heart failure, diuretics in heart failure, low-dose dopamine, equal.

Original ResearchOriginal Research

Continuous Infusion of Furosemide Combined with Low-Dose Dopamine Compared to Intermittent Boluses in Acutely Decompensated Heart Failure is Less Nephrotoxic and Carries a Lower Readmission at Thirty DaysEmad F. aziz, Carlos l. alviar, Eyal HErzog, Juan Pablo Cordova, JosEPH H. bastawrosE, CHaitHanya K. PamidimuKala, andrE toJino, tErrEnCE s. ParK, dan musat, marriCK KuKin

The ACAP Program, Division of Cardiology, St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians & Surgeons, New York, NY, USA

Introduction: Furosemide is a potent loop diuretic that is widely used in the management of heart failure. Several reports have suggested that continuous intravenous administration of loop diuretics may be superior to intermittent administration. In addition the effect of low-dose dopamine to improve renal perfusion might be of benefit to this patient cohort.Methods: We retrospectively evaluated 116 consecutive cardiac care unit patients, who were admitted with acute decompensated heart failure and were divided into two equal groups according to diuretic protocol. Group A patients received furosemide by continuous infusion combined with low-dose dopamine infusion. Group B patients received bolus therapy of intravenous furosemide. The effect on renal function and read-mission rate was recorded.Results: Among 116 patients (60% males, average age 71, range 46-96 years) 41% had ischemic cardio-myopathy, NYHA functional Class was 3.5 ± 0.5 and average EF was 21% ± 7%. On admission, patients in Group A had creatinine (Cr) 2.3 ± 0.2 mg/dL, blood urea nitrogen (BUN) 49.2 ± 25 mg/100 ml and me-dian b-type natriuretic peptid (BNP) 1340 pg/mL, compared to group B patients with Cr 1.7 ± 1.2 mg/dL, BUN 32 ± 22 mg/100 ml and median BNP 1106 pg/mL. The average furosemide dose in group A was 7.9 ± 3.5 mg/hr compared to 7.6 ± 2.7 mg/hr for group B (p=NS). At the end of the study, patients in group A had lower Cr 1.8 ± 0.9 (p=0.0001), lower BUN 43.6 ± 22.9 (p=NS), an increase in estimated glomer-ular filtration rate 57.4 ± 27.4, a shorter hospital stay (p=0.015) and lower readmission rates at 30 days (p=0.0003).Conclusions: Continuous infusion of furosemide in addition to low-dose dopamine is safe, effective and less nephrotoxic than intermittent boluses in patients admitted with acute decompensated heart failure and por-tends a shorter hospital stay and lower readmission rates at 30 days.

A cute decompensated heart failure (ADHF) constitutes one of the major causes for hospitalization in

the United States, representing an impor-tant epidemiological and economic burden for the healthcare system with an annual

age-adjusted incidence of 29 cases per 1000 person-years.1 In 2008, the estimated to-tal cost of heart failure (HF) in the United States was $37.2 billion.2 An important ob-jective in HF management is to optimize therapy for stabilization and a shorter hos-

228 • HJC (Hellenic Journal of Cardiology)

C. Alviar et al

pital stay with lower rates of complications and read-mission using evidence-based pharmacological and de-vice therapy.3,4 The presence of volume overload with a positive fluid balance constitutes an important prog-nostic factor that is usually associated with poor out-comes.5-8 Thus, intravenous diuretic administration has become the mainstay of therapy for the volume over-load associated with ADHF.

A vast amount of evidence is available showing the clear benefit of diuretics, especially loop diuretics such as furosemide, in the setting of ADHF accompa-nied by volume overload. In patients with pulmonary edema, fluid restriction and diuretic therapy has been shown to promote a faster resolution of symptoms and clinical improvement, and has also been associ-ated with a decrease in intubation time and intensive care unit (ICU) stay.9,10 For volume resolution, dif-ferent protocols of diuretic therapy in HF have been used, with the two main strategies including continu-ous infusions and boluses. Results have demonstrat-ed that both therapies are effective when trying to achieve a negative fluid balance in patients with vol-ume overload, with some data indicating superior-ity of furosemide infusion over boluses; however, the differences in safety and side effects between the two protocols have been described to be minimal and sta-tistically insignificant. Nevertheless, to date it is not known which is the preferred protocol in terms of re-nal function preservation or whether the use of low doses of dopamine could carry an additional bene-ficial effect. Therefore, the aim of this study was to evaluate retrospectively the effect of continuous in-fusion of furosemide in addition to low doses of do-pamine infusion in terms of safety and effectiveness, compared to the standardized use of intermittent fu-rosemide boluses, as defined by nephrotoxicity and 30-day readmission rates.

Methods

Patient population

One hundred fifty patients consecutively admitted with the diagnosis of ADHF with volume overload to the cardiac care unit (CCU) were retrospectively screened for this study. Their medical records were reviewed for data, including initial labs (b-type na-triuretic peptide, potassium, and complete blood cell count), initial electrocardiogram, the reason for their screening in the CCU, admission weight, as well as daily weights, follow-up labs and detailed urine out-

put. Of the initial total, 116 patients had complete records and were included in the final analysis. For this analysis, patients were divided into two groups according to the diuretic protocol utilized by the ad-mitting team. Group A included patients receiving furosemide by continuous infusion combined with low-dose dopamine infusion. Group B included pa-tients who received bolus therapy of intravenous fu-rosemide. Exclusion criteria were thrombocytopenia; allergy or contraindications to the use of dopamine and/or furosemide; terminal conditions, such as can-cer with poor prognosis of survival at 1 year; severe electrolyte abnormalities, such as potassium >5.5 mmol/L or <2.5 mmol/L, or sodium on admission >150 mmol/L or <120 mmol/L; severe hypotension; the need for the use of vasopressors or positive ino-tropic agents other than low doses of dopamine; and the use of other diuretics in combination to furose-mide.

Diuretic protocols

The selection of the diuretic protocol employed for each patient was based on the clinical practice in our CCU and depended on the severity of the disease and the de-gree of renal function as determined by creatinine levels. Patients in group A were often sicker and had on aver-age higher creatinine levels on admission; they received furosemide infusion starting at 0.2-0.4 mg/kg/hr in com-bination with dopamine infusion at doses of 1-2 µg/kg/min. Furosemide doses were titrated according to the clinical response to diuresis and to signs of volume over-load. Patients requiring higher doses of dopamine for blood pressure support were excluded from the study.

Group B patients were treated with boluses of IV furosemide based on the novel heart failure path-way utilized at our institution;11 boluses were titrated based on diuresis and clinical response. In those indi-viduals taking oral furosemide in the outpatient set-tings, the conversion from the oral to the intravenous dose used the algorithm of our pathway.12

Endpoints

The co-primary endpoints in our study included nephrotoxicity, determined by the rise in blood urea nitrogen and creatinine levels, and readmission rates for heart failure decompensation at a 30-day follow up. Secondary endpoints were the effect on delta weight change, length of hospital stay, and all cause mortality at 90 days.


Diuretic Therapy and Acute Decompensated Heart Failure

Statistical analysis

Statistical analysis was performed using a standard statistical software package (SPSS for Windows, ver-sion 17; SPSS; Chicago, IL, USA). Continuous vari-ables are expressed as mean ± SD. Normally distrib-uted variables were compared by ANOVA. Categori-cal variables were expressed as a percentage of the to-tal sample and compared using the chi-square test or Fisher’s exact test, as appropriate. The baseline pre-dictors of the primary outcome were selected using stepwise variable selection. Comparison of the two study groups with respect to the change from baseline to secondary endpoints was performed using Wilcox-on rank sum tests. The log-rank test was used to com-pare the two study groups statistically with respect to the time until the first occurrence of either compo-nent of the secondary composite endpoint. Relative risks were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) and were calculated us-ing the Cox proportional hazards model.13 A p-value <0.05 was considered statistically significant.

Results

Demographic parameters are shown in Table 1. Among the 116 patients, 60% were males; the mean age was 71 years. Forty-one percent of the patients had ischemic cardiomyopathy. The New York Heart Association (NYHA) functional class was 3.5 ± 0.5, and the average ejection fraction was 21 ± 7%. Labo-ratory values on admission from all patients included an average admission sodium of 139 ± 5.2 mEq/L, po-tassium 4.7 ± 0.8 mEq/L, blood urea nitrogen (BUN) 44 ± 27 mg/dL, creatinine 1.9 ± 1 mg/dL and b-type natriuretic peptide (BNP) 1589 ± 1160 pg/mL. The two treatment groups each included 58 patients; base-line variables are reported in Table 1. When com-pared to group B, group A had worse kidney func-tion (creatinine on admission 2.3 ± 0.2 vs. 1.7 ± 1.2 mg/dL, p=0.072), and significantly lower estimated glomerular filtration rate (eGFR) (40 ± 15 vs. 63 ± 33 mL/min per 1.73 m2, p=0.00001), with higher ad-mission potassium (4.7 ± 0.8 vs. 4.3 ± 0.5 mmol/L, p=0.004). Group A also had elevated troponin (1.9

Table 1. Patient demographics and baseline findings.

Parameter Group A (n=58) Group B (n=58) p

Demographics:Age, yrs 71 ± 15 71 ± 13 0.953Sex, men (%) 39 (67) 29 (50) 0.062Hypertension (%) 54 (93) 49 (85) 0.115Diabetes mellitus (%) 33 (57) 27 (46) 0.227Smoking (%) 27 (46) 35 (60) 0.523Body mass index, kg/m2 30 ± 8 27 ± 7 0.068Hyperlipidemia (%) 14 (24) 23 (40) 0.073

Heart failure indices: NYHA Class 3.2 ± 0.5 3.1 ± 0.5 0.853LVEF, % 19.5 ± 7 22.5 ± 7 0.551Ischemic etiology (%) 29 (50) 18 (31) 0.293Median BNP, pg/mL 1340 1106 0.193Excess weight on admission, kg 5.2 ± 3.2 6.3 ± 3.8 0.107

Kidney function: Creatinine, mg/dL 2.3 ± 0.2 1.7 ± 1.2 0.072Blood urea nitrogen, mg/dL 49 ± 25 32 ± 22 0.0002eGFR, mL/min/1.73 m2 40 ± 15 63 ± 33 0.00001

Admission laboratory values: Sodium, mmol/L 139 ± 6 139 ± 4 0.951Potassium, mmol/L 4.7 ± 0.8 4.3 ± 0.5 0.004Chloride, mmol/L 103 ± 6 104 ± 5 0.836Troponin, ng/mL 1.9 ± 5.6 0.08 ± 0.1 0.026Creatine kinase (CK-MB), ng/mL 15 ± 18 3.8 ± 2.7 0.002

Home medications: Hydrochlorothiazide (%) 1 (1.7) 3 (5.2) 0.313Furosemide (%) 19 (32) 14 (24) 0.307Spironolactone (%) 4 (7) 0 (0) 0.044

BNP – B-type natriuretic peptide; eGFR – estimated glomerular filtration rate; LVEF – left ventricular ejection fraction; NYHA – New York Heart Association.


C. Alviar et al

± 5.6 vs. 0.08 ± 0.1, p=0.026) and higher creatine ki-nase-MB, (15 ± 18 vs. 3.8 ± 2.7 ng/mL, p=0.002). The average furosemide dose in-group A was 7.9 ± 3.5 mg/hr compared to 7.6 ± 2.7 mg/hr for group B (p=0.77). Patients in group B received higher initial doses of furosemide than group A (71 ± 13 mg vs. 42 ± 28 mg, p=0.035). Hourly urinary output was significantly higher in group A than group B (147 ± 72 ml/hr vs.91 ± 27 ml/hr, p<0.00001).

Primary endpoints

Patients in group A had lower creatinine (p=0.006), lower BNP levels (p<0.015) and higher eGFR (p<0.0006) when compared to patients in group B (Table 2). The delta change in creatinine values from admission to discharge was more favorable for group A (-0.45) when compared to group B (+0.87, p=0.00001), as was the delta change in BUN for group A (-5.66) vs. group B (+10.31, p=0.0001) and the delta change in eGFR (+17.4 for group A and -21.8 for group B, p<0.00001; Figure 1). These results are particularly significant considering that patients in group A had evidence of worse renal function on admission. Importantly, group A patients had a great-er delta change in admission weight when compared to group B (7.3 kg versus 4.0 kg, p<0.0001). Group A patients also had significantly lower readmission rates when followed for a 30-day period (17.2% vs. 48.3%, p=0.0003; Figure 2), with HR 0.45 (95% CI: 0.22 to 0.90, p=0.023) as shown by a Kaplan-Meier curve (Figure 3).

Secondary endpoints

Forty-three (37%) patients reached the secondary outcome of combined readmission at 30 days and mortality at 90 days, with the majority occurring in group B (48% versus 25%, p=0.012; HR 0.50 95% CI: 0.27 to 0.94, p=0.031; Figure 4). Not surprising-ly, patients treated with furosemide and dopamine infusion had a shorter duration of hospital stay (6.8 vs. 9.41 days, p=0.0001). There was a trend toward lower all-cause mortality at the end of the follow-up period (6% vs. 14%, p=0.08). Based on a logistic re-gression module for predictors of endpoints, diabet-ics (HR 2.2, 95% CI: 0.89 to 5.35, p=0.08) and group B patients who had diuretics boluses (HR 4.7, 95% CI: 1.87 to 11.71, p=0.0009) were more likely to have worse outcomes.

Discussion

Heart failure incidence has increased in the last de-cades, with an estimated 5.3 million patients in the United States suffering from this condition and about half a million patients newly diagnosed every year.2 Similarly, ADHF is one of the leading causes for hos-pitalization in the USA and contributes in great per-centage to the economic burden of public health.14,15 During acute decompensation, these patients present with volume overload requiring diuretic therapy rou-tinely at high doses. Thus, the prompt identification of patients admitted with a positive fluid balance who will benefit from diuretic administration is a key point

Table 2. Treatment plans. Differences between groups regarding the effects on the predetermined endpoints before hospital discharge.

Group A (n=58) Group B (n=58) p

Treatment plans: Initial furosemide bolus (mg, iv) 42.4 ± 28.1 70.6 ± 13.3 0.035Mean furosemide dose (mg/hr) 7.9 ± 3.5 7.6 ± 2.7 0.776Mean dopamine dose (µg/kg/hr) 2.48 ± 0.89 0 0.00001

Concomitant medical therapy: Hydrochlorothiazide (%) 14 (24) 6 (10) 0.061Spironolactone (%) 5 (7) 7 (12) 0.546Hydralazine (%) 6 (10) 8 (14) 0.572

Effects of treatment: Average urine output, ml/hr 147 ± 72 91 ± 27 0.00001Creatinine, mg/dl 1.8 ± 0.9 2.6 ± 1.9 0.006Blood urea nitrogen, mg/dl 44 ± 23 43 ± 24 0.796eGFR, ml/min/1.73 m2 57 ± 27 41± 23 0.0006BNP, pg/ml 670 ± 565 1133 ± 1307 0.012Delta change in weight, kg 7.3 ± 4.0 4.0 ± 4.5 0.0001

Abbreviations as in Table 1.



of management and might influence outcomes, as we have previously demonstrated.16 The beneficial effect of diuretic therapy in HF is well known, especially in acute settings such as post myocardial infarction pa-tients and patients with volume overload.17 Furose-mide, a loop diuretic that acts on the Na+-K+-2Cl- co-transporter in the thick ascending limb of the loop of Henle to inhibit sodium and chloride reabsorption, exerts its major effect during acute pulmonary ede-ma by achieving a potent diuretic action.18 However, its efficacy goes beyond its renal action, as manifest-ed by its hemodynamic effects in improving vascular congestion. Dikshit et al demonstrated that the im-mediate action in relieving pulmonary congestion in congestive heart failure starts by relieving ventricular filling pressures and by changing venous capacitance, even before causing changes in natriuresis or free wa-ter clearance.19

Several reports have evaluated the efficacy of a continuous infusion of intravenous furosemide versus

intermittent boluses, based on questions raised from evidence showing a wide dose-response curve of this pharmacological agent.20 It has been proposed that the rate of furosemide delivery to the kidney tissue, both renal corpuscle and tubules, is a main factor in-fluencing diuretic response. This was demonstrated in healthy individuals, in whom furosemide infusion was associated with higher total urinary volume, natriure-sis and kaliuresis.21,22 Dormans et al reported simi-lar results favoring continuous infusion over boluses for treatment of severe heart failure.23 Conversely, a study done in patients post cardiac surgery showed no significant pharmacodynamic differences when com-paring infusion versus boluses. These data, however, came from a study that neither used a crossover de-sign nor employed a loading dose of diuretic in order to avoid confounding factors.24 Similarly, a recent pa-per reported no difference between the two modali-ties, although a higher furosemide dose requirement was found in the group of patients receiving boluses.

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Figure 1. Observed effects on estimated glomerular filtration rate (eGFR), creatinine (Cr), and b-type natriuretic peptide (BNP) in rela-tion to the treatment plans studied. A. Continuous furosemide infusion in addition to low dose dopamine. B. Furosemide boluses.

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C. Alviar et al

These authors did not report any differences in terms of mortality and changes in renal function.25 Simi-larly, Easer et al found no difference between the di-uretic effect of bolus or continuous infusion, and re-ported that there was no difference in the level of neurohormonal activation with either therapy, ex-cept for pro-atrial natriuretic factor, which decreased more during the initial 8 hours of bolus therapy.26

It can be argued that the type of patients includ-ed in the cohorts analyzed might explain some of the conflicting results observed between studies. For in-stance, some of these cohorts included patients with volume overload secondary to heart failure, renal in-sufficiency or both—a fact that can clearly influence the outcomes in terms of fluid balance and nephro-toxicity, as explained above. When evaluating the whole spectrum of studies performed, animal stud-ies, for example, have reported increased diuresis and natriuresis with infusion therapy, and at the same time higher concentrations of serum creatinine when this type of therapy was employed,27 while studies in healthy individuals have shown superiority of infusion over boluses.21 In patients with renal failure, some au-thors have found that continuous intravenous infu-sion of furosemide had significantly better natriuret-ic and diuretic effects than bolus administration of the same dose of the drug in patients with advanced chronic renal insufficiency.28 However, Schuller et al found that intravenous furosemide therapy by either infusion or bolus did not show any difference in terms of fluid balance goals in a cohort of patients with vol-ume overload of cardiac and renal etiologies.29

In terms of patients with congestive heart fail-ure, the overall evidence supports the use of continu-ous furosemide infusion when a gentle diuresis is de-sired.22,23 However, few data are available in terms of side effects and complication rates, especially in those patients in which renal (low-dose) dopamine is concomitantly used with furosemide infusion in order to achieve therapeutic goals with less side ef-fects. Therefore, we considered it important to as-sess whether the use of dopamine in addition to furo-semide infusion had any beneficial effect in terms of nephrotoxicity and readmission rates when compared to furosemide boluses in patients with acute decom-pensated heart failure, as only a few studies have re-ported changes in creatinine levels—also with con-flicting outcomes. One diuretic study found a small statistical increase in creatinine levels in the bolus group,10 while another reported that furosemide in-fusion increases diuresis as well as creatinine levels

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Figure 4. Kaplan-Meier survival curve for all events (readmission and mortality) as a function of treatment plans.

Figure 3. Kaplan-Meier curve for time to readmission as a func-tion of treatment plans.



more than bolus therapy.30 Others, however, report-ed no differences in creatinine levels with either mo-dality.23,31

A major issue in patients with severe heart failure (NYHA Class III and IV) is the lack of response to furosemide, which is not uncommon in clinical prac-tice. This is usually related to impairments in renal function, the use of concomitant medications and al-terations in the metabolism of the drug secondary to altered splanchnic flow.32-36 Thus, different strategies have been proposed to increase the diuretic response in patients with this resistance. For instance, Licata et al demonstrated how the concomitant use of hyper-tonic saline with furosemide infusion positively im-pacted diuresis, morbidity and mortality in patients with severe refractory heart failure,37 Their findings could be explained by an increased stimulation of myocardial function and by a redistribution of the in-travascular volume, as shown by other authors.38,39

Another strategy proposed is the concomitant use of inotropic agents, which are frequently used for pa-tients in the critical care settings who need vasopres-sor support.40 One of the agents commonly used for this purpose is dopamine. It is an endogenous cate-cholamine used by infusion in patients requiring he-modynamic support and acts on a variety of different receptors in the renal, splanchnic, and cardiac or vas-cular tissues, according to the dose employed. When infused at low rates (≤3 µg/kg/min), it selectively stim-ulates receptors in the renal and splanchnic vascula-ture, promoting a higher blood flow in these tissues. Additionally, it provides a natriuretic effect by acting on the tubular epithelial cells independently of the changes in blood flow.41 These renal effects led origi-nally to the use of the so called “renal dose” of dopa-mine infusion in the past, for more than 30 years, with the purpose of preventing or reversing acute kidney injury. However, increasing evidence has led to the conclusion that the use of dopamine at these doses is actually not as effective as thought in patients with acute renal failure. The explanation is that the ben-eficial effects on the renal blood flow and tubular na-triuresis are blunted in patients presenting with acute renal failure, especially those who are oliguric.42

In patients with heart failure, early reports showed a synergistic effect when dopamine was combined with furosemide infusion, since the positive effects of dopa-mine seem to be preserved in patients who do not have compromised renal function.43-45 A study performed in a small number of patients showed that there were no added benefits when combining furosemide infusion

with low doses of dopamine in terms of sodium excre-tion or GFR. Nonetheless, this study included only 6 patients and did not report creatinine levels or readmis-sion data and only reported GFR estimated by insulin clearance.46 A recent publication by Elkayam evaluated the renal effects of intravenous dopamine on 13 patients with chronic heart failure. Renal blood flow was calcu-lated from renal artery cross-sectional area measured with intravascular ultrasound and renal blood flow ve-locity-time integral measured by the intravascular Dop-pler technique. Cross-sectional area increased and was significantly higher than baseline; also the velocity-time integral was significantly higher than baseline at doses of 3 and 5 µg/kg/min. Similarly, renal blood flow increased whereas renal vascular resistance decreased, resulting in an increase in cardiac output. However, the increase in renal blood flow appeared proportionately larger than corresponding increases in cardiac output, suggesting that low-dose dopamine is associated with an increase in renal blood flow in patients with heart failure, likely due to dilation of both the large conductance and small resis-tance renal blood vessels.47

In the present study we found that patients who were receiving continuous furosemide infusion in ad-dition to low-dose dopamine demonstrated less neph-rotoxicity (despite starting with worse renal function), a shorter hospital stay and lower readmission rates at 30 days when compared to patients receiving inter-mittent boluses. Our findings are similar to those re-ported by Coter et al, who evaluated the combination of low doses of dopamine with oral or intravenous fu-rosemide by continuous infusion versus intravenous infusion of furosemide alone in patients with refrac-tory HF. They found that the treatment with furose-mide infusion alone carried higher nephrotoxicity, manifested by creatinine levels and creatinine clearance – worse than the combination of dopamine and furo-semide, either by infusion or oral route. It is notable that the group that received oral furosemide plus do-pamine had a modest elevation in creatinine values and presented less incidence of hypokalemia, while diuretic effectiveness did not differ among the three groups.48 In this study, however, readmission rates were not reported and a study arm receiving furo-semide boluses was not included. As noted by Dor-mans,19 a greater response to continuous infusion oc-curred with equal if not smaller quantities of diuretics excreted in the urine, so that the efficacy of loop di-uretics may be equal if not greater with infusion than with bolus administration. This may be explained by less fluctuation in diuretic plasma levels in continuous


C. Alviar et al

infusions, which results in a smoother, more constant, yet greater diuretic effect relative to the amount of drug excreted in the urine.

We found that those patients who received com-bined therapy had a shorter hospital stay, less neph-rotoxicity and lower readmission rates at 30 days than those receiving only furosemide boluses. This may be multifactorial and related to achieving quicker thera-peutic endpoints, as noted by Schuller et al,7 with the better response to a steady urine output flow and the im-provement in eGFR that are seen with the combination therapy. These findings are more striking when we take into account the fact that those patients who received dopamine and furosemide infusion seemed to be sicker than those who received bolus therapy, as revealed by the baseline levels of creatinine, BUN and BNP.

Our results suggest a synergistic effect from both medications when administered together, with a pos-sible increase in renal perfusion and function.

Limitations

The limitations of our study arise from the retrospec-tive nature of our work, which precluded the use of a randomized design in which the inclusion of a third arm of study receiving both intermittent boluses and low-dose dopamine infusion could add valuable infor-mation. Similarly, we did not focus on outcomes for diuretic or natriuretic effectiveness according to each therapy modality. However, our objective was more towards the evaluation of the role of the renal dose of dopamine, which is not commonly used, in the setting of acute heart failure, and to address whether its com-bination with furosemide infusion has a significant impact on side effects and complications. We con-sider that, in order to resolve questions regarding ef-fectiveness in these specific patients, it would be nec-essary to carry out a prospectively designed, double blind, randomized, two-by-two study with a similar population, including different combinations of bo-lus versus continuous infusion diuretic therapy, with or without renal dose dopamine therapy. Furosemide was used as the sole loop diuretic, so we cannot offer any information on the relative effectiveness of other loop diuretics.

Conclusions

In a retrospectively designed study, we reported a low-er rate of complications driven by less nephrotoxicity, shorter hospital stay and lower readmission rates at

30 days in patients receiving both low-dose dopamine and furosemide infusion when compared to intermit-tent administration of furosemide boluses. However, a complete evaluation of the combination of furosemide and dopamine in patients with congestive heart fail-ure has yet to be made, especially in patients undergo-ing either infusion or boluses of furosemide. Our data merit further investigations with an accurate method-ological design and an appropriate number of subjects, stratified by the degree of heart failure and by the pres-ence or absence of renal dysfunction. This will be the proper way to answer specific questions in terms of ef-fectiveness, safety and complications.

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